PROJECT SUMMARY Pancreatitis and pre-malignant Acinar-to-Ductal Metaplasia (ADM) and Pancreatic Epithelial Neoplasia (PanIN) represent two of the most common and lethal disorders affecting the adult pancreas. It has been postulated that progenitor-like cells in both conditions may play an important role in pancreas regeneration and pre- malignant progression. Therefore, identifying these progenitor cells will be important as they could be used for enhanced regenerative therapies or targeted to prevent tumor formation. However, the identity of these progenitors and their role in normal and diseased pancreas remains unclear. Preliminary data from our lab, using novel multi-color lineage labeled mouse models of the normal and pre-neoplastic pancreas, suggest that tissue renewal in the exocrine pancreas and ADM/PanIN progression may be driven by a subset of growth- advantaged cells. These exciting and novel findings has led us to hypothesize that acinar renewal and PanIN growth in vivo are driven by cellular subsets with progenitor-like characteristics. This hypothesis will be pursued in two interrelated Specific Aims: (1) To delineate the mechanisms of acinar cell self-renewal in the exocrine pancreas. (2) To define the mechanisms of clonal growth during ADM/PanIN Progression. This proposal will utilize novel in vivo lineage labeling techniques combined with 3D culture systems and RNA sequencing technology to elucidate the cellular mechanisms of tissue renewal and pre-neoplastic progression in the panaceas. The experiments in this innovative proposal will also have direct application toward development of novel therapies for the treatment of both benign and malignant pancreatic disorders. In addition, this research proposal will be supported in an integrated manner through exceptional mentorship, an already constituted research advisory committee, training plan and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a strong basis for my career goal to become an independent physician-scientist who is NIH funded at a major academic medical center.